Lantipeptides are peptides that are ribosomally synthesized by bacteria such as staphylococci, lactobacilli, and actinomycetes. The common structural characteristic of lantipeptides is the presence of non-canonical amino acid lanthionine, which confers conformational stability to the peptidic structure. One particular example of lantipeptides is represented by the labyrinthopeptins, which contain the carbacyclic post translationally modified amino acid labionin (Lab). Labionins are formed from two Ser residues and one Cys residue. During the biosynthesis both Serine residues are dehydrated to dehydroalanines (Dha). The C-terminal Cys residue forms a thioether bridge by addition to the central Dha generating an enolate intermediate that then adds to a second N-terminal Dha to form the labionin structure. A first labyrinthopeptin known from the state of the art is Labyrinthopeptin A2 (Meidl et al., Angew. Chem. Int. Ed. 2010, 49, 1151-1154). It consists of 18 amino acids and is strongly hydrophobic.
Labyrinthopeptin A2 has a globular structure that consists primarily of hydrophobic amino acids. Formally, the structure can be dissected in two nonapeptides. Each of these nonapeptides bears a C-terminal Cys residue that forms a disulfide bond.
WO 2008/040469 describes compounds obtainable from Actinomadura namibiensis (DSM6313), that are defined as labyrinthopeptins composed of a highly bridged peptidic structure, 18 amino acids long, whose sequence is XDWXLWEXCXTGXLFAXC, wherein the two Cys residues form a disulfide bridge and each X independently represents one of the non-natural amino acids involved in the bridging linkages. The compounds are described as characterized by antibacterial activity, antiviral activity, as well as activity against neuropathic and inflammatory pain.
The invention provides novel lantipeptide compounds, methods to make such compounds and their use. These and other aspects of the invention are described herein.